Although tuberculosis (TB) has been curable and preventable for nearly 75 years, TB remains a major public health threat globally, as the world?s leading infectious disease cause of death. Goals to ?eliminate? TB by 2035 are unlikely to be achieved in this century with the currently available control strategies. Development of new therapeutic and prevention tools, such as a TB vaccine, is needed, but such efforts are hampered by insufficient understanding of the mechanisms of protection against Mycobacterium tuberculosis (Mtb) infection. Although a host genetic role in protection has long been postulated and family-based linkage studies have had promising results, no specific genes have yet been carefully characterized. Research efforts to date have been limited by challenges in defining clinical phenotypes of Mtb resistance, small sample sizes, and difficulty in measuring the degree of exposure to Mtb. With recent advances in high-throughput micro-array and sequencing technology, however, large-scale genetic studies are now possible. In the proposed study, we will enroll a cohort of 4,000 household contacts who have been recently exposed to active TB disease. We will identify contacts who remain uninfected, despite a well-characterized, high degree of exposure to a TB index case, and compare them with household contacts who become infected with Mtb. The study will take place in the high TB incidence settings of India and South Africa. In Aim 1, we will characterize a phenotype for resistance to Mtb infection using responses to both tuberculin skin test (TST) and interferon-gamma release assays (IGRA) in a cohort recently exposed to a culture-confirmed active TB index case. By integrating these TST and IGRA results with rigorous characterization of contacts? exposure to active TB index cases, we will be able to identify individuals who have resisted Mtb infection despite a high degree of exposure. In Aim 2, we will conduct a genome-wide association study (GWAS) to identify common and rare genetic variants associated with resistance to Mtb infection. We will also investigate the candidate SNPs in previously reported TB-related genetic loci. In Aim 3, we will leverage the emerging field of metabolomics to identify metabolic profiles that distinguish individuals resistant to Mtb infection. Identification of metabolic clusters associated with resistance will reveal cellular pathways involved in resisting or clearing Mtb infection, and will also enhance the GWAS findings by providing a functional output of the downstream effects of any genetic polymorphisms. This unbiased and integrated approach will provide an unprecedented opportunity to identify genes and pathways involved in resistance to Mtb infection, and understand the multi-layered molecular mechanisms underlying TB infection. Our research team has more than a decade of experience conducting TB, household contact, genomics and metabolomics studies that will allow us to achieve the innovative scientific aims of this study.